6-Arylmethyl-substituted pyrazolopyrimidines

ABSTRACT

The invention relates to novel 6-arylmethyl-substituted pyrazolopyrimidines, process for their preparation and their use for producing medicaments for improving perception, concentration, learning and/or memory.

This application is a continuation of U.S. Ser. No. 10/556,437 filedOct. 10, 2006, which is incorporated herein by reference.

The invention relates to novel 6-arylmethyl-substitutedpyrazolopyrimidines, process for their preparation and their use forproducing medicaments for improving perception, concentration, learningand/or memory.

Inhibition of phosphordiesterases modulates the levels of the cyclicnucleotides 5′-3′ cyclic adenosine monophosphate (cAMP) and 5′-3′ cyclicguanosine monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP)are important second messengers and therefore play a central role incellular signal transduction cascades. Each of them reactivates interalia, but not exclusively, protein kinases. The protein kinase activatedby cAMP is called protein kinase A (PKA), and the protein kinaseactivated by cGMP is called protein kinase G (PKG). Activated PKA andPKG are able in turn to phosphorylate a number of cellular effectorproteins (e.g. ion channels, G-protein-coupled receptors, structuralproteins). It is possible in this way for the second messengers cAMP andcGMP to control a wide variety of physiological processes in a widevariety of organs. However, the cyclic nucleotides are also able to actdirectly on effector molecules. Thus, it is known, for example, thatcGMP is able to act directly on ion channels and thus is able toinfluence the cellular ion concentration (review in: Wei et al., Prog.Neurobiol., 1998, 56: 37-64). The phosphodiesterases (PDE) are a controlmechanism for controlling the activity of cAMP and cGMP and thus in turnthese physiological processes. PDEs hydrolyse the cyclic monophosphatesto the inactive monophosphates AMP and GMP. At least 21 PDE genes havenow been described (Exp. Opin. Investig. Drugs 2000, 9, 1354-3784).These 21 PDE genes can be divided on the basis of their sequencehomology into 11 PDE families (for proposed nomenclature, seehttp://depts.washington.edu/pde/Nomenclature.html.). Individual PDEgenes within a family are differentiated by letters (e.g. PDE1A andPDE1B). If different splice variants within a gene also occur, this isthen indicated by an additional numbering after the letters (e.g.PDE1A1).

Human PDE9A was cloned and sequenced in 1998. The amino acid identitywith other PDEs does not exceed 34% (PDE8A) and is never less than 28%(PDE5A). With a Michaelis-Menten constant (Km) of 170 nM, PDE9A has highaffinity for cGMP. In addition, PDE9A is selective for cGMP (Km forcAMP=230 mM). PDE9A has no cGMP binding domain, suggesting allostericenzyme regulation by cGMP. It was shown in a Western blot analysis thatPDE9A is expressed in humans inter alia in testes, brain, smallintestine, skeletal muscle, heart, lung, thymus and spleen. The highestexpression was found in the brain, small intestine, heart and spleen(Fisher et al., J. Biol. Chem., 1998, 273 (25): 15559-15564). The genefor human PDE9A is located on chromosome 21q22.3 and comprises 21 exons.To date, 4 alternative splice variants of PDE9A have been identified(Guipponi et al., Hum. Genet., 1998, 103: 386-392). Classical PDEinhibitors do not inhibit human PDE9A. Thus, IBMX, dipyridamole,SKF94120, rolipram and vinpocetine show no inhibition on the isolatedenzyme in concentrations of up to 100 μM. An IC₅₀ of 35 μM has beendemonstrated for zaprinast (Fisher et al., J. Biol. Chem., 1998, 273(25): 15559-15564).

Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (J.Biol. Chem., 1998, 273 (19): 15553-15558). This has, like the humanform, high affinity for cGMP with a Km of 70 nM. Particularly highexpression was found in the mouse kidney, brain, lung and heart. MurinePDE9A is not inhibited by IBMX in concentrations below 200 μM either;the IC₅₀ for zaprinast is 29 mM (Soderling et al., J. Biol. Chem., 1998,273 (19): 15553-15558). It has been found that PDE9A is stronglyexpressed in some regions of the rat brain. These include olfactorybulb, hippocampus, cortex, basal ganglia and basal forebrain (Andreevaet al., J. Neurosci., 2001, 21 (22): 9068-9076). The hippocampus, cortexand basal forebrain in particular play an important role in learning andmemory processes.

As already mentioned above, PDE9A is distinguished by havingparticularly high affinity for cGMP. PDE9A is therefore active even atlow physiological concentrations, in contrast to PDE2A (Km=10 μM;Martins et al., J. Biol. Chem., 1982, 257: 1973-1979), PDE5A (Km=4 μM;Francis et al., J. Biol. Chem., 1980, 255: 620-626), PDE6A (Km=17 μM;Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17): 8133-8141) andPDE11A (Km=0.52 μM; Fawcett et al., Proc. Nat. Acad. Sci., 2000, 97 (7):3702-3707). In contrast to PDE2A (Murashima et al., Biochemistry, 1990,29: 5285-5292), the catalytic activity of PDE9A is not increased by cGMPbecause it has no GAF domain (cGMP-binding domain via which the PDEactivity is allosterically increased) (Beavo et al., Current Opinion inCell Biology, 2000, 12: 174-179). PDE9A inhibitors may therefore lead toan increase in the baseline cGMP concentration.

WO 98/40384 discloses pyrazoleopyrimidines which are PDE1, 2 and 5inhibitors and can be employed for the treatment of cardiovascular andcerebrovascular disorders and disorders of the urogenital system.

CH 396 924, CH 396 925, CH 396 926, CH 396 927, DE 1 147 234, DE 1 149013, GB 937,726 describe pyrazoleopyrimidines which have acoronary-dilating effect and which can be employed for the treatment ofdisturbances of myocardial blood flow.

U.S. Pat. No. 3,732,225 describes pyrazoleopyrimidines which have anantiinflammatory and blood glucose-lowering effect.

DE 2 408 906 describes styrylpyrazoleopyrimidines which can be employedas antimicrobial and antiinflammatory agents for the treatment of, forexample, oedema.

The present invention relates to compounds of the formula

in which

-   R¹ is phenyl, pyridyl or thiophenyl which are optionally substituted    by up to 3 substituents independently of one another selected from    the group of C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, cyano,    trifluoromethyl, amino, nitro, hydroxy, C₁-C₆-alkylamino, halogen,    C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,    C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,    C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,    heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino,    C₁-C₆-alkylsulphonyl, C₁-C₆-alkylthio,    -   where C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylamino,        C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,        C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,        C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,        heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino,        C₁-C₆-alkylsulphonyl and C₁-C₆-alkylthio are optionally        substituted by a radical selected from the group of hydroxy,        cyano, halogen, hydroxycarbonyl and a group of the formula        —NR³R⁴,    -   where    -   R³ and R⁴ are independently of one another hydrogen or        C₁-C₆-alkyl,    -   or    -   R³ and R⁴ together with the nitrogen atom to which they are        bonded are 5- to 8-membered heterocyclyl,-   R² is phenyl or heteroaryl, where phenyl is substituted by 1 to 3    radicals and heteroaryl is optionally substituted by 1 to 3 radicals    in each case independently of one another selected from the group of    C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl,    amino, nitro, hydroxy, C₁-C₆-alkylamino, halogen,    C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,    C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,    C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,    heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino,    C₁-C₆-alkylsulphonyl and C₁-C₆-alkylthio,    -   where C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylamino,        C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,        C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,        C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,        heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino,        C₁-C₆-alkylsulphonyl and C₁-C₆-alkylthio are optionally        substituted by a radical selected from the group of hydroxy,        cyano, halogen, hydroxycarbonyl and a group of the formula        —NR³R⁴,        -   where R³ and R⁴ have the meanings indicated above, and the            salts, solvates and/or solvates of the salts thereof.

The compounds of the invention may, depending on their structure, existin stereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and respectivemixtures thereof. The sterically pure constituents can be isolated in aknown manner from such mixtures of enantiomers and/or diastereomers.

Salts which are preferred for these purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds (I) include acidaddition salts of mineral acids, carboxylic acids and sulphonic acids,e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also include saltsof conventional bases such as, by way of example and preferably, alkalimetal salts (e.g. sodium and potassium salts), alkaline earth metalsalts (e.g. calcium and magnesium salts) and ammonium salts derived fromammonia or organic amines having 1 to 16 C atoms, such as, by way ofexample and preferably, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, dehydroabietylamine, arginine,lysine, ethylenediamine and methylpiperidine.

Solvates refers for the purposes of the invention to those forms of thecompounds which form, in the solid or liquid state, a complex bycoordination with solvent molecules. Hydrates are a specific form ofsolvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents have thefollowing meaning, unless specified otherwise:

C₁-C₆-Alkoxy is a straight-chain or branched alkoxy radical having 1 to6, preferably 1 to 4, particularly preferably having 1 to 3 carbonatoms. Preferred examples include methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C₁-C₆Alkyl is a straight-chain or branched alkyl radical having 1 to 6,preferably 1 to 4, particularly preferably 1 to 3, carbon atoms.Preferred examples include methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorine,bromine are preferred, and fluorine and chlorine are particularlypreferred.

C₁-C₆-Alkylamino is a straight-chain or branched mono- or dialkylaminoradical having 1 to 6, preferably 1 to 4 and particularly preferablyhaving 1 to 3 carbon atoms. Preferred examples include methylamino,ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino and n-hexylamino, dimethylamino, diethylamino,di-n-propylamino, diisopropylamino, di-t-butylamino, di-n-pentylamino,di-n-hexylamino, ethylmethylamino, isopropylmethylamino,n-butylethylamino and n-hexyl-1-pentylamino.

C₁-C₆-Alkylcarbonylamino is an alkylcarbonyl radical linked via an aminogroup, where the alkyl radical may be straight-chain or branched andcomprises 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3,carbon atoms. Preferred examples include methylcarbonylamino,ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino,tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

C₁-C₆-Alkylaminocarbonyl is a mono- or dialkylamino radical linked via acarbonyl group, where the alkyl radicals may be identical or different,are straight-chain or branched and each comprise 1 to 6, preferably 1 to4 and particularly preferably 1 to 3, carbon atoms. Preferred examplesinclude methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl,n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,di-n-propylaminocarbonyl, diisopropylaminocarbonyl,di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl,di-n-hexylaminocarbonyl, ethylmethylaminocarbonyl,isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl andn-hexyl-1-pentylaminocarbonyl. A further possibility in the case of adialkylamino radical is for the two alkyl radicals to form together withthe nitrogen atom to which they are bonded a 5- to 8-memberedheterocyclyl.

C₆-C₁₀-Arylaminocarbonyl is an arylamino radical linked via a carbonylgroup. Preferred examples include phenylaminocarbonyl andnaphthylaminocarbonyl.

C₆-C₁₀-Arylcarbonylamino is an arylcarbonyl radical linked via an aminogroup. Preferred examples include phenylcarbonylamino andnaphthylcarbonylamino.

C₁-C₆-Alkylsulphonylamino is a straight-chain or branchedalkylsulphonylamino radical having 1 to 6, preferably 1 to 4 andparticularly preferably having 1 to 3, carbon atoms. Preferred examplesinclude methylsulphonylamino, ethylsulphonylamino,n-propylsulphonylamino, isopropylsulphonylamino,tert-butylsulphonylamino, n-pentylsulphonylamino andn-hexylsulphonylamino.

C₁-C₆-Alkylsulphonyl is a straight-chain or branched alkylsulphonylradical having 1 to 6, preferably 1 to 4 and particularly preferablyhaving 1 to 3, carbon atoms. Preferred examples include methylsulphonyl,ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,tert-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl.

C₁-C₆-Alkylthio is a straight-chain or branched alkylthio radical having1 to 6, preferably 1 to 4 and particularly preferably having 1 to 3,carbon atoms. Preferred examples include methylthio, ethylthio,n-propylthio, isopropylthio, tert-butylthio, n-pentylthio andn-hexylthio.

Heteroaryl is an aromatic, mono- or bicyclic radical having 5 to 10 ringatoms and up to 5 heteroatoms from the series S, O and/or N. 5- to6-membered heteroaryls having up to 4 heteroatoms are preferred. Theheteroaryl radical may be bonded via a carbon or nitrogen atom.Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl andisoquinolinyl.

Heteroarylaminocarbonyl is a heteroarylamino radical linked via acarbonyl group. Preferred examples include thienylaminocarbonyl,furylaminocarbonyl, pyrrolylaminocarbonyl, thiazolylaminocarbonyl,oxazolylaminocarbonyl, imidazolylaminocarbonyl, tetrazolylaminocarbonyl,pyridylaminocarbonyl, pyrimidinylaminocarbonyl,pyridazinylaminocarbonyl, indolylaminocarbonyl, indazolylaminocarbonyl,benzofuranylaminocarbonyl, benzothiophenylaminocarbonyl,quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.

Heteroarylcarbonylamino is a heteroarylcarbonyl radical linked via anamino group. Preferred examples include thienylcarbonylamino,furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino,oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino,pyridylcarbonylamino, pyrimidinylcarbonylamino,pyridazinylcarbonylamino, indolylcarbonylamino, indazolylcarbonylamino,benzofuranylcarbonylamino, benzothiophenylcarbonylamino,quinolinylcarbonylamino and isoquinolinylcarbonylamino.

5- to 8-membered heterocyclyl is a mono- or polycyclic heterocyclicradical having 5 to 8 ring atoms and up to 3, preferably 2, heteroatomsor hetero groups from the series N, O, S, SO, SO₂. Mono- or bicyclicheterocyclyl is preferred. Monocyclic heterocyclyl is particularlypreferred. N and O are preferred as heteroatoms. The heterocyclylradicals may be saturated or partially unsaturated. Saturatedheterocyclyl radicals are preferred. 5- to 7-membered heterocyclylradicals are particularly preferred. Preferred examples includeoxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl,tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl,morpholinyl, perhydroazepinyl.

6-membered heteroaryl is an aromatic radical having 6 ring atoms and upto 2 nitrogen atoms. The heteroaryl radical is bonded via a carbon atom.Preferred examples include pyridyl, pyrimidinyl, pyridazinyl andpyrazinyl.

When radicals in the compounds of the invention are optionallysubstituted, unless otherwise specified substitution by up to threeidentical or different substituents is preferred.

The compounds of the invention may also be in the form of tautomers asshown by way of example below:

A further embodiment of the invention relates to compounds of theformula (I)

in which

-   R¹ is phenyl, pyridyl or thiophenyl, which are optionally    substituted by up to 3 radicals independently of one another    selected from the group of C₁-C₄-alkyl, C₁-C₄-alkoxy,    hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy,    C₁-C₄-alkylamino, fluorine, chlorine, bromine,    C₆-C₁₀-arylcarbonylamino, C₁-C₄-alkylcarbonylamino,    C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkoxycarbonyl,    C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,    heteroarylcarbonylamino, C₁-C₄-alkylsulphonylamino,    C₁-C₄-alkylsulphonyl, C₁-C₄-alkylthio,    -   where C₁-C₄-alkyl and C₁-C₄-alkoxy are optionally substituted by        a radical selected from the group of hydroxy, cyano, fluorine,        chlorine, bromine, hydroxycarbonyl and a group of the formula        —NR³R⁴,        -   where        -   R³ and R⁴ are independently hydrogen or C₁-C₄-alkyl, or        -   R³ and R⁴ together with the nitrogen atom to which they are            bonded are 5- to 6-membered heterocyclyl,-   R² is phenyl, pyrimidyl or pyridyl, where phenyl is substituted by 1    to 3 radicals and pyrimidyl and pyridyl are optionally substituted    by 1 to 3 radicals in each case independently of one another    selected from the group of C₁-C₄-alkyl, C₁-C₄-alkoxy,    hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy,    C₁-C₄-alkylamino, fluorine, chlorine, bromine,    C₆-C₁₀-arylcarbonylamino, C₁-C₄-alkylcarbonylamino,    C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkoxycarbonyl,    C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,    heteroarylcarbonylamino, C₁-C₄-alkylsulphonylamino,    C₁-C₄-alkylsulphonyl, C₁-C₄-alkylthio,    -   where C₁-C₄-alkyl and C₁-C₄-alkoxy are optionally substituted by        a radical selected from the group of hydroxy, cyano, fluorine,        chlorine, bromine, hydroxycarbonyl and a group of the formula        —NR³R⁴,        -   where R³ and R⁴ have the meanings indicated above,            and the salts, solvates and/or solvates of the salts            thereof.

A further embodiment of the invention relates to compounds of theformula (I)

in which R¹ has the meanings indicated above, and

-   R² is phenyl or pyridyl, where phenyl is substituted by 1 to 2    radicals and pyridyl is optionally substituted by 1 to 2 radicals in    each case independently of one another selected from the group of    methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine    and chlorine,    and the salts, solvates and/or solvates of the salts thereof.

A further embodiment of the invention relates to compounds of theformula (I), in which

-   R¹ is phenyl, pyridyl or thiophenyl, which are optionally    substituted by up to 2 radicals independently of one another    selected from the group of C₁-C₄-alkyl, fluorine, chlorine,    trifluoromethyl, hydroxy, phenylcarbonylamino,    C₁-C₄-alkylcarbonylamino, C₁-C₄-alkylaminocarbonyl or    phenylaminocarbonyl,-   R² is phenyl or pyridyl, where phenyl is substituted by 1 to 2    radicals and pyridyl is optionally substituted by 1 to 2 radicals in    each case independently of one another selected from the group of    methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine    and chlorine,    and the salts, solvates and/or solvates of the salts thereof.

A process for preparing compounds of the invention of the formula (I)has also been found, characterized in that either

[A] compounds of the formula

-   -   in which    -   R² has the meanings indicated above,    -   are converted by reaction with a compound of the formula

R¹—CH₂—C(O)-Z  (IIIa),

-   -   in which    -   R¹ has the meanings indicated above,    -   and    -   Z is chlorine or bromine,    -   in an inert solvent and in the presence of a base, initially        into compounds of the formula

-   -   in which    -   R¹ and R² have the meanings indicated above,    -   and then cyclized in an inert solvent in the presence of a base        to compounds of the formula (I),        or        [B] compounds of the formula (II) are reacted with a compound of        the formula

R¹—CH₂—C(O)—OR³  (IIIb),

-   -   in which    -   R¹ has the meanings indicated above,    -   and    -   R³ is methyl or ethyl,    -   in an inert solvent and in the presence of a base, with direct        cyclization to (I),        or        [C] compounds of the formula

-   -   in which    -   R² has the meanings indicated above,    -   are converted initially by reaction with a compound of the        formula (IIIa) in an inert solvent and in the presence of a base        into compounds of the formula

-   -   in which    -   R¹ and R² have the meanings indicated above,    -   and the latter are cyclized in a second step in an inert solvent        and in the presence of a base and of an oxidizing agent to (I),        and the resulting compounds of the formula (I) are where        appropriate reacted with the appropriate (i) solvents        and/or (ii) bases or acids to give their solvates, salts and/or        solvates of the salts.

Suitable for the first step of process [A] and of process [C] are inertorganic solvents which are not changed under the reaction conditions.These preferably include ethers such as, for example, diethyl ether,dioxane, tetrahydrofuran or glycol dimethyl ether, or toluene orpyridine. It is likewise possible to employ mixtures of the solventsmentioned. Tetrahydrofuran, toluene or pyridine are particularlypreferred.

Generally suitable bases are alkali metal hydrides such as, for example,sodium hydride, or cyclic amines such as, for example, piperidine,pyridine, dimethylaminopyridine (DMAP) or C₁-C₄-alkylamines such as, forexample, triethylamine. Sodium hydride, pyridine and/ordimethylaminopyridine are preferred.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompounds of the formula (II) or (V).

In one variant, the reaction is carried out in pyridine to which acatalytic amount of DMAP is added. It is also possible where appropriateto add toluene.

The reaction temperature can generally be varied within a relativelywide range. It is generally in a range from −20° C. to +200° C.,preferably from 0° C. to +100° C.

Solvents suitable for the cyclization in the second step of processes[A] and [C] are the usual organic solvents. These preferably includealcohols such as methanol, ethanol, propanol, isopropanol, n-butanol ortert-butanol, or ethers such as tetrahydrofuran or dioxane, ordimethylformamide or dimethyl sulphoxide. Alcohols such as methanol,ethanol, propanol, isopropanol or tert-butanol are particularlypreferably used. It is likewise possible to employ mixtures of thesolvents mentioned.

Bases suitable for the cyclization in the second step of processes [A]and [C] are the usual inorganic bases. These preferably include alkalimetal hydroxides or alkaline earth metal hydroxides such as, forexample, sodium hydroxide, potassium hydroxide or barium hydroxide, oralkali metal carbonates such as sodium or potassium carbonate or sodiumbicarbonate, or alkali metal alcoholates such as sodium methanolate,sodium ethanolate, potassium methanolate, potassium ethanolate orpotassium tert-butanolate. Potassium carbonate, sodium hydroxide andpotassium tert-butanolate are particularly preferred.

When carrying out the cyclization, the base is generally employed in anamount of from 2 mol to 6 mol, preferably from 3 mol to 5 mol, in eachcase based on 1 mol of the compounds of the formula (IV) or (VI).

Oxidizing agents suitable for the cyclization in the second step ofprocess [C] are, for example, hydrogen peroxide or sodium borate.Hydrogen peroxide is preferred.

The cyclization in processes [A], [B] and [C] is generally carried outin a temperature range from 0° C. to +160° C., preferably at the boilingpoint of the particular solvent.

The cyclization is generally carried out under atmospheric pressure.However, it is also possible to carry out the process under elevatedpressure or under reduced pressure (e.g. in a range from 0.5 to 5 bar).

Solvents suitable for process [B] are the alcohols mentioned above forthe second step of processes [A] and [C], with preference for ethanol.

Bases suitable for process [B] are alkali metal hydrides such as, forexample, sodium or potassium hydride, or alkali metal alcoholates suchas, for example, sodium methanolate, ethanolate, isopropoxide orpotassium tert-butoxide. Sodium hydride is preferred.

The base is employed in an amount of from 2 mol to 8 mol, preferablyfrom 3 mol to 6 mol, in each case based on 1 mol of the compounds of theformula (II).

The compounds of the formula (II) are known or can be prepared forexample by initially condensing ethoxymethylenemalonoxnitrile withhydrazine derivatives of the formula

R²—NH—NH₂  (VII),

in whichR² has the meanings indicated above,in an inert solvent to give pyrazolecarbonitriles of the formula (V),and then reacting the latter with one of the oxidizing agents mentionedabove, preferably hydrogen peroxide, in the presence of ammonia [cf.,for example, A. Miyashita et al., Heterocycles 1990, 31, 1309ff].

The compounds of the formulae (IIIa), (IIIb) and (VII) are commerciallyavailable, known from the literature or can be prepared in analogy toprocesses known from the literature.

The process of the invention can be illustrated by way of example by thefollowing formula scheme:

Further processes for preparing pyrazoleo[3,4-d]pyrimidin-4-ones areknown and can likewise be employed for synthesizing the compounds of theinvention (see, for example: P. Schmidt et al., Helvetica Chimica Acta1962, 189, 1620ff.).

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted. They are distinguished inparticular by inhibition of PDE9A.

It has surprisingly been found that the compounds of the invention aresuitable for producing medicaments for improving perception,concentration, learning or memory.

The compounds of the invention can, by reason of their pharmacologicalproperties, be employed alone or in combination with other medicamentsfor improving perception, concentration, learning and/or memory.

The compounds of the invention are particularly suitable for improvingperception, concentration, learning or memory after cognitiveimpairments like those occurring in particular insituations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumatic dementia,general concentration impairments, concentration impairments in childrenwith learning and memory problems, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, includingPick's syndrome, Parkinson's disease, progressive nuclear palsy,dementia with corticobasal degeneration, amyotropic lateral sclerosis(ALS), Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia orKorsakoff's psychosis.

The in vitro effect of the compounds of the invention can be shown withthe following biological assays:

PDE Inhibition

Recombinant PDE1C (GenBank/EMBL Accession Number: NM_(—)005020, Loughneyet al. J. Biol. Chem. 1996 271, 796-806), PDE2A (GenBank/EMBL AccessionNumber: NM_(—)002599, Rosman et al. Gene 1997 191, 89-95), PDE3B(GenBank/EMBL Accession Number: NM_(—)000922, Miki et al. Genomics 1996,36, 476-485), PDE4B (GenBank/EMBL Accession Number: NM_(—)002600,Obernolte et al. Gene. 1993, 129, 239-247), PDE5A (GenBank/EMBLAccession Number: NM_(—)001083, Loughney et al. Gene 1998, 216,139-147), PDE7B (GenBank/EMBL Accession Number: NM_(—)018945, Hetman etal. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476), PDE8A(GenBank/EMBL Accession Number: AF 056490, Fisher et al. Biochem.Biophys. Res. Commun. 1998 246, 570-577), PDE9A (Fisher et al., J. Biol.Chem., 1998, 273 (25): 15559-15564), E10A (GenBank/EMBL AccessionNumber: NM_(—)06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45),PDE11A (GenBank/EMBL Accession Number: NM_(—)016953, Fawcett et al.Proc. Natl. Acad. Sci. 2000, 97, 3702-3707) were expressed in Sf9 cellswith the aid of the pFASTBAC baculovirus expression system (GibcoBRL).

The test substances are dissolved in 100% DMSO and serially diluted todetermine their in vitro effect on PDE 9A. Typically, serial dilutionsfrom 200 μM to 1.6 μM are prepared (resulting final concentrations inthe assay: 4 μM to 0.032 μM). 2 μL portions of the diluted substancesolutions are introduced into the wells of microtiter plates (Isoplate;Wallac Inc., Atlanta, Ga.). Then 50 μL of a dilution of the PDE9Apreparation described above are added. The dilution of the PDE9Apreparation is chosen so that less than 70% of the substrate isconverted during the subsequent incubation (typical dilution: 1:10000;dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl₂, 1.7 mM EDTA, 0.2%BSA). The substrate, [8-³H] guanosine 3′,5′-cyclic phosphate (1 μCi/μL;Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 withassay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl₂, 1.7 mM EDTA) to aconcentration of 0.0005 μCi/μL. The enzyme reaction is finally startedby adding 50 μL (0.025 μCi) of the diluted substrate. The assay mixturesare incubated at room temperature for 60 min and the reaction is stoppedby adding 25 μl of a PDE9A inhibitor (e.g. the inhibitor frompreparation example 1, final concentration 10 μM) dissolved in assaybuffer. Immediately thereafter, 25 μL of a suspension containing 18mg/mL Yttrium Scintillation Proximity Beads (Amersham PharmaciaBiotech., Piscataway, N.J.) are added. The microtiter plates are sealedwith a film and left to stand at room temperature for 60 min. The platesare then measured for 30 s per well in a Microbeta scintillation counter(Wallac Inc., Atlanta, Ga.). IC₅₀ values are determined from thegraphical plot of the substance concentration versus the percentageinhibition.

Representative examples of the inhibiting effect of the compounds of theinvention on PDE9A are listed by means of the IC₅₀ values in Table 1:

TABLE 1 Example IC₅₀ [nM] 2 50 4 64 9 <30 21 <30

The in vitro effect of test substances on recombinant PDE3B, PDE4B,PDE7B, PDE8A, PDE10A and PDE11A is determined in accordance with theassay protocol described above for PDE 9A with the followingadaptations: [5′,8-³H] adenosine 3′,5′-cyclic phosphate (1 μCi/μL;Amersham Pharmacia Biotech., Piscataway, N.J.) is used as substrate.Addition of an inhibitor solution to stop the reaction is unnecessary.Instead, the incubation of substrate and PDE is followed immediately byaddition of the yttrium scintillation proximity beads as described aboveand thus the reaction is stopped. To determine a corresponding effect onrecombinant PDE1C, PDE2A and PDE5A, the protocol is additionally adaptedas follows: with PDE1C, additionally 10⁻⁷ M calmodulin and 3 mM CaCl₂are added to the reaction mixture. PDE2A is stimulated in the assay byadding 1 μM cGMP and is assayed with a BSA concentration of 0.01%. Thesubstrate employed for PDE1C and PDE2A is [5′,8-³H] adenosine3′,5′-cyclic phosphate (1 μCi/μL; Amersham Pharmacia Biotech.,Piscataway, N.J.), and for PDE5A is [8-³H] guanosine 3′,5′-cyclicphosphate (1 μCi/μL; Amersham Pharmacia Biotech., Piscataway, N.J.).

Long-Term Potentiation

Long-term potentiation is regarded as a cellular correlate of learningand memory processes. The following method can be used to determinewhether PDE 9 inhibition has an influence on long-term potentiation:

Rat hippocampi are placed at an angle of about 70 degrees to the cuttingblade (chopper). 400 μm-thick slices of the hippocampus are prepared.The slices are removed from the blade using a very soft, thoroughlywetted brush (marten hair) and transferred into a glass vessel with coldnutrient solution (124 mM NaCl, 4.9 mM KCl, 1.3 mM MgSO₄*7H₂O, 2.5 mMCaCl²⁺ anhydrous, 1.2 mM KH₂PO₄, 25.6 mM NaHCO₃, 10 mM glucose, pH 7.4)gassed with 95% O₂/5% CO₂. During the measurement, the slices are keptin a temperature-controlled chamber under a 1-3 mm-high liquid level.The flow rate is 2.5 ml/min. The preliminary gassing takes place under aslightly elevated pressure (about 1 atm) and through a microneedle inthe prechamber. The slice chamber is connected to the prechamber in sucha way that a minicirculation can be maintained. The minicirculation isdriven by the 95% O₂/5% CO₂ flowing out through the microneedle. Thefreshly prepared hippocampus slices are adapted in the slice chamber at33° C. for at least 1 hour.

The stimulus level is chosen so that the focal excitatory postsynapticpotentials (FEPSP) are 30% of the maximum excitatory postsynapticpotential (EPSP). A monopolar stimulation electrode consisting oflacquered stainless steel, and a constant-current biphasic stimulusgenerator (AM Systems 2100) are used for local stimulation of theSchaffer collaterals (voltage: 1-5 V, pulse width of one polarity 0.1ms, total pulse 0.2 ms). Glass electrodes (borosilicate glass withfilament, 1-5 MOhm, diameter: 1.5 mm, tip diameter: 3-20 μm), filledwith normal nutrient solution, are used to record the excitatorypostsynaptic potentials (FEPSP) from the stratum radiatum. The fieldpotentials are measured versus a chlorinated silver reference electrodelocated at the edge of the slice chamber using a DC voltage amplifier.The field potentials are filtered through a low-pass filter (5 kHz). Theslope of the fEPSPs (FEPSP slope) is determined for the statisticalanalysis of the experiments. The recording, analysis and control of theexperiment takes place with the aid of a software program (PWIN) whichwas developed in the Department of Neurophysiology. The formation of theaverage FEPSP slopes at the respective time points and construction ofthe diagrams takes place with the aid of the EXCEL software, withautomatic data recording by an appropriate macro.

Superfusion of the hippocampus slices with a 10 mM solution of thecompounds of the invention leads to a significant increase in the LTP.

The in vivo effect of the compounds of the invention can be shown forexample as follows:

Social Recognition Test

The social recognition test is a learning and memory test. It measuresthe ability of rats to distinguish between known and unknown members ofthe same species. This test is therefore suitable for examining thelearning- or memory-improving effect of the substances of the invention.

Adult rats housed in groups are placed singly in test cages 30 minbefore the start of the test. Four min before the start of the test, thetest animal is put in an observation box. After this adaptation time, ajuvenile animal is put in with the test animal and the absolute time forwhich the adult animal inspects the young one is measured for 2 min(trial 1). All behaviours clearly directed at the young animal aremeasured, i.e. anogenital inspection, pursuit and grooming, during whichthe old animal was no further than 1 cm from the young animal. Thejuvenile is then removed, and the adult is treated with a compound ofthe invention or vehicle and subsequently returned to its own cage. Thetest is repeated after a retention time of 24 hours (trial 2). Adiminished social interaction time compared with trial 1 indicates thatthe adult rat remembers the young animal.

The adult animals receive intraperitoneal injections either at a fixedtime interval (e.g. 1 hour) before trial 1 or directly following trial 1either with vehicle (10% ethanol, 20% Solutol, 70% physiological saline)or 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg or 3.0 mg/kg compound of theinvention dissolved in 10% ethanol, 20% Solutol, 70% physiologicalsaline. Vehicle-treated rats show no reduction in the social interactiontime in trial 2 compared with trial 1. They have consequently forgottenthat they have already had contact with the young animal. Surprisingly,the social interaction time in the second run after treatment with thecompounds of the invention is significantly reduced compared with thosetreated with vehicle. This means that the substance-treated rats haveremembered the juvenile animal and thus the compounds of the inventiondisplay an improving effect on learning and memory.

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable excipients or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of theformulation, i.e. in amounts which are sufficient to reach the stateddose range.

The formulations are produced for example by extending the activeingredients with solvents and/or excipients, where appropriate with useof emulsifiers and/or dispersants, it being possible for example whenwater is used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration can take place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behaviour towards themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

Unless indicated otherwise, all quantitative data relate to percentagesby weight. Solvent ratios, dilution ratios and concentration data ofliquid/liquid solutions are based in each case on volume. The statement“w/v” means “weight/volume”. Thus, for example, “10% w/v” means: 100 mlof solution or suspension contain 10 g of substance.

ABBREVIATIONS

-   DCI direct chemical ionization (in MS)-   DMSO dimethyl sulphoxide-   ESI electrospray ionization (in MS)-   Fp. melting point-   h hour(s)-   HPLC high pressure, high performance liquid chromatography-   LC-MS coupled liquid chromatography-mass spectroscopy-   min minutes-   MS mass spectroscopy-   NMR nuclear magnetic resonance spectroscopy-   R_(t) retention time (in HPLC)-   TLC thin-layer chromatography

LC-MS Methods: Method 1

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100;column: Grom-Sil 120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A: 1 l ofwater+1 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile+1ml of 50% formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min;UV detection: 208-400 nm.

Method 2

Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100;column: Grom-Sil 1200DS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A: 1 l water+1ml 50% strength formic acid, eluent B: 1 l acetonitrile+1 ml 50%strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min;UV detection: 208-400 nm.

Method 3

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2790; column: Grom-Sil 1200DS-4 HE, 50×2 mm, 3.0 μm; eluent B:acetonitrile+0.05% formic acid, eluent A: water+0.05% formic acid;gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min 90% B→5.5 min 90% B; oven:45° C.; flow rate: 0.0 min 0.75 ml/min→4.5 min 0.75 ml/min→5.5 min 1.25ml/min; UV detection: 210 nm.

Method 4:

MS apparatus type: Micromass TOF (LCT); HPLC apparatus type: 2-columnswitching, Waters 2690; column: YMC-ODS-AQ, 50 mm×4.6 mm, 3.0 μm; eluentA: water+0.1% formic acid, eluent B: acetonitrile+0.1% formic acid;gradient: 0.0 min 100% A→0.2 min 95% A→1.8 min 25% A→1.9 min 10% A→3.2min 10% A; oven: 40° C.; flow rate: 3.0 ml/min; UV detection: 210 nm.

Method 5:

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2790; column: Grom-Sil 1200DS-4 HE 50 mm×2 mm, 3.0 μm; eluent B:acetonitrile+500 μl of 50% formic acid/l, eluent A: water+500 μl of 50%formic acid/l; gradient: 0.0 min 0% B→0.2 min 0% B→2.9 min 70% B→3.1 min90% B→4.5 min 90% B; oven: 50° C.; flow rate: 0.8 ml/min; UV detection:210 nm.

Method 6

MS apparatus type: Micromass ZQ; HPLC apparatus type: TSP P4000, TSPAS300, TSP UV3000; column: Grom-Sil 1200DS-4 HE, 50 mm×2 mm, 3.0 μm;eluent A: water+250 μl of 50% strength formic acid/1, eluent B:acetonitrile+250 μl of 50% strength formic acid/1; gradient: 0.0 min 0%B→0.2 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B; oven: 50° C.;flow rate: 0.8 ml/min; UV detection: 210 nm.

Starting Compounds Example 1A5-Amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

3.0 g (17.3 mmol) of 2,6-dimethylphenylhydrazine hydrochloride aresuspended with 2.1 g (17.3 mmol) of ethoxymethylenemalononitrile in 40ml of ethanol, and 7.3 ml (52.1 mmol) of triethylamine are added. Thereaction mixture is heated to reflux for 3 h, during which a clearsolution forms. After cooling to room temperature, diethyl ether isadded to this. The triethylammonium chloride which precipitates isfiltered off. The solvent is removed in vacuo, and the residue ispurified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm; eluent A: water,eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%B). 2.3 g (62% of theory) of the product are obtained as yellowcrystals.

LC-MS (Method 6): R_(t)=2.77 min.

MS (ESI pos): m/z=213 (M+H)⁺.

Example 2A 5-Amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 2.08 g (56% of theory) ofthe desired product are obtained starting from 3 g (17.4 mmol) of2,3-dimethylphenylhydrazine hydrochloride, 2.1 g (17.4 mmol) ofethoxymethylenemalononitrile and 7.3 ml (52.1 mmol) of triethylamine.

LC-MS (Method 6): R_(t)=2.79 min.

MS (ESI pos): m/z=213 (M+H)⁺.

Example 3A 5-Amino-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 2.16 g (57% of theory) ofthe desired product are obtained starting from 3 g (18.9 mmol) of4-methylphenylhydrazine hydrochloride, 2.3 g (18.9 mmol) ofethoxymethylenemalononitrile and 7.9 ml (56.7 mmol) of triethylamine.

LC-MS (Method 1): R_(t)=3.0 min.

MS (ESI pos): m/z=199 (M+H)⁺.

Example 4A 5-Amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 2.9 g (83% of theory) ofthe desired product are obtained starting from 3 g (14.1 mmol) of2,6-dichlorophenylhydrazine hydrochloride, 1.7 g (14.1 mmol) ofethoxymethylenemalononitrile and 5.8 ml (42.2 mmol) of triethylamineafter purification by column chromatography (mobile phasedichloromethane/methanol 98:2).

LC-MS (Method 3): R_(t)=2.8 min.

MS (ESI pos): m/z=253 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.82 (s, 2H), 7.59 (m, 2H), 7.69 (m, 1H),7.80 (s, 1H) ppm.

Example 5A 5-Amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 2.2 g (51% of theory) ofthe desired product are obtained starting from 3 g (16.9 mmol) of2,5-dichlorophenylhydrazine, 2.0 g (16.9 mmol) ofethoxymethylenemalononitrile and 7.1 ml (50.8 mmol) of triethylamine.

LC-MS (Method 1): R_(t)=3.2 min.

MS (ESI pos): m/z=253 (M+H)⁺.

Example 6A 5-Amino-1-(2-nitrophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 1.9 g (53% of theory) ofthe desired product are obtained starting from 3 g (15.8 mmol) of2-nitrophenylhydrazine hydrochloride, 1.93 g (16.9 mmol) ofethoxymethylenemalononitrile and 6.6 ml (47.6 mmol) of triethylamine.

LC-MS (Method 1): R_(t)=2.80 min.

MS (ESI pos): m/z=230 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.87 (s, 2H), 7.72 (m, 1H), 7.77 (s, 1H),7.78 (m, 1H), 7.88 (m, 1H), 8.16 (dd, 1H) ppm.

Example 7A 5-Amino-1-(3-fluorophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 1.5 g (31% of theory) ofthe desired product are obtained starting from 4 g (24.6 mmol) of3-fluorophenylhydrazine hydrochloride, 3 g (24.6 mmol) ofethoxymethylenemalononitrile and 10.3 ml (73.8 mmol) of triethylamine.

LC-MS (Method 1): R_(t)=2.90 min.

MS (ESI pos): m/z=203 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.81 (s, 2H), 7.28 (m, 1H), 7.36 (m, 2H),7.57 (m, 1H), 7.80 (s, 1H) ppm.

Example 8A 5-Amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 1A, 0.4 g (53% of theory) ofthe desired product are obtained starting from 0.6 g (4.17 mmol) of3-chloro-2-pyridylhydrazine, 0.51 g (4.17 mmol) ofethoxymethylenemalononitrile and 1.1 ml (8.3 mmol) of triethylamine andafter purification by column chromatography (mobile phasedichloromethane/methanol 98:2).

LC-MS (Method 6): R_(t)=2.17 min.

MS (ESI pos): m/z=220 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.87 (s, 2H), 7.63 (dd, 1H), 7.79 (s, 1H),8.22 (dd, 1H), 8.54 (dd, 1H) ppm.

Example 9A 5-Amino-1-(2-methylphenyl)-1H-pyrazole-4-carbonitrile

10.2 g (64.4 mmol) of 2-methylphenylhydrazine hydrochloride aresuspended with 7.8 g (64.4 mmol) of ethoxymethylenemalononitrile in 100ml of methanol, and 26.9 ml (193.3 mmol) of triethylamine are added. Thereaction mixture is heated to reflux overnight, during which a clearsolution forms. The solution is subsequently distilled off under reducedpressure, and the crude product is purified by column chromatography(silica gel, mobile phase dichloromethane). 10.8 g (85% of theory) ofthe desired product are obtained.

LC-MS (Method 1): R_(t)=3.10 min.

MS (ESI pos): m/z=199 (M+H)⁺.

Example 10A 5-Amino-1-(2-ethylphenyl)-1H-pyrazole-4-carbonitrile

A solution of 3.0 g (17.0 mmol) of 2-ethylphenylhydrazine hydrochlorideand 2.12 g (17.0 mmol) of ethoxymethylenemalononitrile in 36 ml ofethanol is mixed with 7.1 ml (51.1 mmol) of triethylamine and heated at60° C. until the reaction is complete according to a TLC check (about 30min). For working up, the solvent is stripped off, and the residue istaken up in dichloromethane, washed with saturated sodium bicarbonatesolution and dried over sodium sulphate. Concentration results in acrude product which is purified by column chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol). 3.05 g (83.5% oftheory) of the desired product are obtained.

m.p.: 130° C.

MS (ESI pos): m/z=213 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.0 (t, 3H), 2.35 (q, 2H), 6.4 (s, 2H),7.2-7.5 (m, 4H), 7.7 (s, 1H) ppm.

Example 11A5-Amino-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 10A, 5.02 g (76.9% of theory)of the desired product are obtained starting from 4.8 g (25.9 mmol) of2-trifluoromethylphenylhydrazine hydrochloride, 3.16 g (25.9 mmol) ofethoxymethylenemalononitrile and 7.2 ml (51.7 mmol) of triethylamine.

m.p.: 190° C.

MS (ESI pos): m/z=253 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.6 (s, 2H), 7.5 (d, 1H), 7.7-8.0 (m, 4H)ppm.

Example 12A 5-Amino-1-(2-fluorophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 10A, 5.13 g (88% purity, 84% oftheory) of the desired product are obtained starting from 5.0 g (30.8mmol) of 2-fluorophenylhydrazine hydrochloride, 3.27 g (26.7 mmol) ofethoxymethylenemalononitrile and 11.3 ml (81.3 mmol) of triethylamine.

MS (ESI pos): m/z=203 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.7 (s, 2H), 7.3-7.6 (m, 4H), 7.8 (s, 1H)ppm.

Example 13A 5-Amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 10A, 4.64 g (78% of theory) ofthe desired product are obtained starting from 5.0 g (27.1 mmol) of2-chlorophenylhydrazine hydrochloride, 3.31 g (27.1 mmol) ofethoxymethylenemalononitrile and 11.3 ml (81.3 mmol) of triethylamine.

m.p.: 135° C.

MS (ESI pos): m/z=219 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.6 (s, 2H), 7.45-7.75 (m, 4H), 7.8 (s, 1H)ppm.

Example 14A 5-Amino-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 10A, 2.3 g (46.6% of theory) ofthe desired product are obtained starting from 3.0 g (26.7 mmol, 97%purity) of 2-hydrazinopyridine, 3.26 g (26.7 mmol) ofethoxymethylenemalononitrile and 7.4 ml (53.3 mmol) of triethylamine.

m.p.: 193° C.

MS (ESI pos): m/z=186 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=7.35 (m, 1H), 7.8-8.12 (m, 3H), 8.15 (s,2H), 8.5 (m, 1H) ppm.

Example 15A 5-Amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile

In analogy to the preparation of Example 10A, 3.5 g (88% of theory) ofthe desired product are obtained starting from 4.1 g (18 mmol) of2-methoxyphenylhydrazine hydrochloride, 2.19 g (18 mmol) ofethoxymethylenemalononitrile and 10 ml (71.9 mmol) of triethylamine.

m.p.: 129° C.

MS (ESI pos): m/z=215 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.8 (s, 3H), 6.3 (s, 2H), 7.05 (t, 1H), 7.2(d, 1H), 7.25 (d, 1H), 7.5 (t, 1H), 7.7 (s, 1H) ppm.

Example 16A 5-Amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide

2 g (9.4 mmol) of5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 1A)are dissolved in 25 ml of ethanol, and a mixture of 20 ml of 30%strength hydrogen peroxide and 40 ml of 25% strength ammonia is added.The solution is stirred at room temperature overnight and thenconcentrated to about 15 ml in a rotary evaporator. The oily emulsionresulting thereby is taken up in dichloromethane. It is washed severaltimes with water and saturated sodium thiosulphate solution. Drying overmagnesium sulphate is followed by removal of the solvent in vacuo. Theresidue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm;eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min30% B, 50 min 95% B). 0.88 g (40% of theory) of the product is obtainedas colourless solid.

LC-MS (Method 1): R_(t)=2.6 min.

MS (ESI pos): m/z=231 (M+H)⁺.

Example 17A 5-Amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 1.29 g (70% of theory) ofthe desired product are obtained from 1.5 g (7.1 mmol) of5-amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 2A)in a mixture of 25 ml of ethanol, 10 ml of 30% strength hydrogenperoxide and 40 ml of 25% strength ammonia.

LC-MS (Method 1): R_(t)=2.7 min.

MS (ESI pos): m/z=231 (M+H)⁺.

Example 18A 5-Amino-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 1.02 g (47% of theory) ofthe desired product are obtained from 2 g (10.1 mmol) of5-amino-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile (Example 3A) in amixture of 25 ml of ethanol, 20 ml of 30% strength hydrogen peroxide and40 ml of 25% strength ammonia.

LC-MS (Method 1): R_(t)=2.7 min.

MS (ESI pos): m/z=217 (M+H)⁺.

Example 19A 5-Amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 1.6 g (74% of theory) ofthe desired product are obtained from 2 g (7.9 mmol) of5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonitrile (Example 4A)in a mixture of 25 ml of ethanol, 10 ml of 30% strength hydrogenperoxide and 40 ml of 25% strength ammonia by crystallization from thereaction solution.

LC-MS (Method 1): R_(t)=2.5 min.

MS (ESI pos): m/z=271 (M+H)⁺.

Example 20A 5-Amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 2.02 g (94% of theory) ofthe desired product are obtained from 2 g (7.9 mmol) of5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonitrile (Example 5A)in a mixture of 25 ml of ethanol, 18 ml of 30% strength hydrogenperoxide and 40 ml of 25% strength ammonia by crystallization from thereaction solution.

LC-MS (Method 1): R_(t)=2.80 min.

MS (ESI pos): m/z=271 (M+H)⁺.

Example 21A 5-Amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 1.4 g (86% of theory) ofthe desired product are obtained from 1.5 g (6.5 mmol) of5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carbonitrile (Example 6A) in amixture of 25 ml of ethanol, 16 ml of 30% strength hydrogen peroxide and40 ml of 25% strength ammonia by crystallization from the reactionsolution.

LC-MS (Method 1): R_(t)=2.3 min.

MS (ESI pos): m/z=248 (M+H)⁺.

Example 22A 5-Amino-1-(2-aminophenyl)-1H-pyrazole-4-carboxamide

1.28 g (5.27 mmol) of5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxamide (Example 21A) areintroduced into 30 ml of ethyl acetate and stirred with 5.8 g (25.8mmol) of tin(II) chloride dihydrate at 70° C. for 16 hours. Aftercooling to room temperature, the solution is adjusted to pH 9-10 withsaturated sodium bicarbonate solution. The tin salts precipitatedthereby are filtered off through kieselguhr. The filtrate is extractedwith ethyl acetate. The combined organic phases are washed withsaturated sodium chloride solution. After drying over sodium sulphate,the solvent is removed in vacuo. 0.82 g (72% of theory) of the desiredproduct is obtained.

LC-MS (Method 2): R_(t)=3.0 min.

MS (ESI pos): m/z=218 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=5.04 (s, 2H), 6.00 (s, 2H), 6.66 (m, 1H),6.89 (m, 1H), 7.03 (m, 2H), 7.92 (s, 1H) ppm.

Example 23A 5-Amino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 1.1 g (75% of theory) ofthe desired product are obtained from 1.3 g (6.4 mmol) of5-amino-1-(3-fluorophenyl)-1H-pyrazole-4-carbonitrile (Example 7A) in amixture of 25 ml of ethanol, 10 ml of 30% strength hydrogen peroxide and40 ml of 25% strength ammonia by crystallization from the reactionsolution.

LC-MS (Method 1): R_(t)=2.60 min.

MS (ESI pos): m/z=221 (M+H)⁺.

Example 24A 5-Amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 0.29 g (66% of theory) ofthe desired product are obtained from 0.4 g (1.8 mmol) of5-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carbonitrile (Example 8A)in a mixture of 7 ml of ethanol, 5 ml of 30% strength hydrogen peroxideand 7 ml of 25% strength ammonia.

LC-MS (Method 2): R_(t)=3.00 min.

MS (ESI pos): m/z=238 (M+H)⁺.

¹H-NMR (300 MHz, DMSO-d₆): δ=6.42 (s, 2H), 7.58 (dd, 1H), 7.88 (s, 1H),8.20 (dd, 1H), 8.53 (dd, 1H) ppm.

Example 25A 5-Amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide

300 ml of 96% strength sulphuric acid are cautiously added to 40.0 g(201.8 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carbonitrile(Example 9A) while cooling in ice. The mixture is then heated to 40° C.and stirred for 2 hours at this temperature. After cooling, it is pouredinto 2 l of ice-water and cautiously neutralized with 50% strengthsodium hydroxide solution. After extraction with ethyl acetate threetimes (2 l each time) the combined organic phases are washed withsaturated sodium chloride solution and dried over sodium sulphate, andthe solvent is distilled off under reduced pressure. 36.0 g (82% oftheory) of product (purity >90%) are obtained and are employed withoutfurther purification in subsequent reactions.

LC-MS (Method 6): R_(t)=2.14 min.

MS (ESI pos): m/z=217 (M+H)⁺.

Example 26A 5-Amino-1-(2-ethylphenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 2.58 g (87% of theory) ofthe desired product are obtained from 2.75 g (12.8 mmol) of5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carbonitrile (Example 10A) in amixture of 106 ml of ethanol, 27 ml of 30% strength hydrogen peroxideand 133 ml of 25% strength ammonia after chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol).

m.p.: 147° C.

MS (ESI pos): m/z=231 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.0 (t, 3H), 2.4 (q, 2H), 5.95 (s, 2H), 6.3(broad d, 2H), 7.2-7.5 (m, 4H), 7.8 (s, 1H) ppm.

Example 27A5-Amino-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 4.01 g (87% of theory) ofthe desired product are obtained from 5.0 g (19.8 mmol) of5-amino-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile (Example11A) in a mixture of 195 ml of ethanol, 49 ml of 30% strength hydrogenperoxide and 244 ml of 25% strength ammonia after chromatography onsilica gel (mobile phase dichloromethane with 0-10% methanol).

m.p.: 186° C.

MS (ESI pos): m/z=271 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.1 (s, 2H), 7.0 (broad d, 2H), 7.45-8.0(m, 5H) ppm.

Example 28A 5-Amino-1-(2-fluorophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 3.89 g (81% of theory) ofthe desired product are obtained from 5.0 g (21.9 mmol, 89% purity) of5-amino-1-(2-fluorophenyl)-1H-pyrazole-4-carbonitrile (Example 12A) in amixture of 173 ml of ethanol, 43 ml of 30% strength hydrogen peroxideand 216 ml of 25% strength ammonia after chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol).

m.p.: 181° C.

MS (ESI pos): m/z=221 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.2 (s, 2H), 7.0 (broad d, 2H), 7.3-7.6 (m,4H), 7.9 (s, 1H) ppm.

Example 29A 5-Amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 3.93 g (79% of theory) ofthe desired product are obtained from 4.6 g (21.0 mmol) of5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile (Example 13A) in amixture of 159 ml of ethanol, 39 ml of 30% strength hydrogen peroxideand 198 ml of 25% strength ammonia after chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol).

m.p.: 166° C.

MS (ESI pos): m/z=237 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=6.1 (s, 2H), 7.0 (broad d, 2H), 7.4-7.7 (m,4H), 7.85 (s, 1H) ppm.

Example 30A 5-Amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 2.28 g (90% of theory) ofthe desired product are obtained from 2.3 g (12.4 mmol) of5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile (Example 14A) in amixture of 90 ml of ethanol, 23 ml of 30% strength hydrogen peroxide and113 ml of 25% strength ammonia after chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol).

m.p.: 218° C.

MS (DCI): m/z=204 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=7.1 (broad d, 2H), 7.3 (dd, 1H), 7.5 (s,2H), 7.85 (d, 1H), 7.95 (s, 1H), 8.0 (dd, 1H), 8.45 (d, 1H) ppm.

Example 31A 5-Amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide

In analogy to the preparation of Example 16A, 2.61 g (70% of theory) ofthe desired product are obtained from 3.5 g (16.0 mmol, 98% purity) of5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile (Example 15A) ina mixture of 172 ml of ethanol, 34 ml of 30% strength hydrogen peroxideand 137 ml of 25% strength ammonia after chromatography on silica gel(mobile phase dichloromethane with 0-10% methanol).

m.p.: 191° C.

MS (ESI pos): m/z=233 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.8 (s, 3H), 5.9 (s, 2H), 7.0 (broad s,2H), 7.05-7.55 (m, 4H), 7.8 (s, 1H) ppm.

Exemplary Embodiments Example 16-(3-Chlorobenzyl)-1-(2,6-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

0.1 g (0.43 mmol) of5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 16A)is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3mmol) of methyl 3-chlorophenylacetate and 0.17 g (4.34 mmol) of 60%sodium hydride (suspension in mineral oil) are added. The reactionmixture is heated to reflux overnight. Cooling to room temperature isfollowed by acidification with concentrated hydrochloric acid. Thesodium chloride precipitated thereby is filtered off. The filtrate isconcentrated in vacuo, and the remaining residue is purified bypreparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B:acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 59 mg(37% of theory) of the product are obtained as a colourless solid.

LC-MS (Method 2): R_(t)=4.20 min.

MS (ESI pos): m/z=365 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.87 (s, 6H), 3.92 (s, 2H), 7.29 (m, 7H),8.28 (s, 1H), 12.43 (s, 1H) ppm.

Example 26-(3-Chlorobenzyl)-1-(2,3-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

0.1 g (0.43 mmol) of5-amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 17A)is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3mmol) of methyl 3-chlorophenylacetate and 0.17 g (4.34 mmol) of 60%sodium hydride (suspension in mineral oil) are added. The reactionmixture is heated to reflux overnight. Cooling to room temperature isfollowed by acidification with concentrated hydrochloric acid. Themixture of sodium chloride and the product precipitated thereby isfiltered off and washed several times with water and diethyl ether.Drying under high vacuum results in 97 mg (61% of theory) of the productas colourless solid.

LC-MS (Method 3): R_(t)=3.85 min.

MS (ESI pos): m/z=365 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.82 (s, 3H), 2.32 (s, 3H), 3.92 (s, 2H),7.31 (m, 7H), 8.23 (s, 1H), 12.40 (s, 1H) ppm.

Example 36-(3-Chlorobenzyl)-1-(4-methylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 2, 99 mg (69% of theory) of thedesired product are obtained as a colourless solid starting from 0.88 g(0.41 mmol) of 5-amino-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide(Example 18A), 0.22 g (1.2 mmol) of methyl 3-chlorophenylacetate and0.16 g (4.09 mmol) of 60% sodium hydride.

LC-MS (Method 3): R_(t)=4.03 min.

MS (ESI pos): m/z=351 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.35 (s, 3H), 4.04 (s, 2H), 7.35 (m, 5H),7.50 (s, 1H), 7.89 (d, 2H), 8.23 (s, 1H), 12.49 (s, 1H) ppm.

Example 46-(3-Chlorobenzyl)-1-(2,6-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 1, 104 mg (69% of theory) ofthe desired product are obtained as a colourless solid starting from 0.1g (0.37 mmol) of5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxamide (Example 19A),0.2 g (1.1 mmol) of methyl 3-chlorophenylacetate and 0.14 g (3.6 mmol)of 60% sodium hydride.

LC-MS (Method 3): R_(t)=3.77 min.

MS (ESI pos): m/z=405 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.94 (s, 2H), 7.30 (m, 4H), 7.69 (m, 2H),7.70 (s, 1H), 8.39 (s, 1H), 12.57 (s, 1H) ppm.

Example 56-(3-Chlorobenzyl)-1-(2,5-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 1, 35 mg (23% of theory) of thedesired product are obtained as a colourless solid starting from 0.1 g(0.37 mmol) of 5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxamide(Example 20A), 0.2 g (1.1 mmol) of methyl 3-chlorophenylacetate and 0.14g (3.6 mmol) of 60% sodium hydride.

LC-MS (Method 2): R_(t)=4.20 min.

MS (ESI pos): m/z=405 (M+H)⁺

Example 61-(2-Aminophenyl)-6-(3-chlorobenzyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 1, 103 mg (63% of theory) ofthe desired product are obtained as a colourless solid starting from 0.1g (0.46 mmol) of 5-amino-1-(2-aminophenyl)-1H-pyrazole-4-carboxamide(Example 22A), 0.25 g (1.4 mmol) of methyl 3-chlorophenylacetate and0.18 g (4.6 mmol) of 60% sodium hydride.

LC-MS (Method 6): R_(t)=3.32 min.

MS (ESI pos): m/z=352 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.96 (s, 2H), 4.46 (s, 2H), 6.81 (t, 1H),7.03 (d, 1H), 7.31 (m, 5H), 7.44 (s, 1H), 8.28 (s, 1H), 12.47 (s, 1H)ppm.

Example 76-(3-Chlorobenzyl)-1-(3-fluorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 2, 125 mg (77% of theory) ofthe desired product are obtained as a colourless solid starting from 0.1g (0.45 mmol) of 5-amino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxamide(Example 23A), 0.25 g (1.36 mmol) of methyl 3-chlorophenylacetate and0.18 g (4.5 mmol) of 60% sodium hydride.

LC-MS (Method 3): R_(t)=3.98 min.

MS (ESI pos): m/z=355 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=4.08 (s, 2H), 7.19 (m, 1H), 7.36 (m, 3H),7.55 (m, 2H), 7.93 (m, 2H), 8.3 (s, 1H), 12.61 (s, 1H) ppm.

Example 86-(3-Chlorobenzyl)-1-(3-chloropyridin-2-yl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 2, 85 mg (54% of theory) of thedesired product are obtained as a colourless solid starting from 0.1 g(0.42 mmol) of5-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide (Example24A), 0.23 g (1.26 mmol) of methyl 3-chlorophenylacetate and 0.17 g (4.2mmol) of 60% sodium hydride.

LC-MS (Method 3): R_(t)=3.10 min.

MS (ESI pos): m/z=372 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=4.01 (s, 2H), 7.34 (m, 4H), 7.49 (s, 1H),7.69 (d, 1H), 7.91 (t, 1H), 8.27 (s, 1H), 12.57 (s, 1H) ppm.

Example 96-(2-Bromobenzyl)-1-(2-methylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

2.0 g (9.25 mmol) of5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A) and9.5 g (41.62 mmol) of methyl (2-bromophenyl)acetate are dissolved in 30ml of absolute ethanol under argon, and 3.15 g (46.6 mmol) of sodiumethoxide are added. The reaction mixture is heated to a refluxovernight. Cooling to room temperature is followed by hydrolysis with 50ml of water and subsequent extraction with ethyl acetate (2×50 ml). Thecombined organic phases are dried over sodium sulphate, and the solventis distilled off under reduced pressure. The crude product is thenpurified by column chromatography (silica gel; mobile phasecyclohexane/ethyl acetate, gradient 10:1→1:1). 3.01 g (82% of theory) ofthe product are obtained.

LC-MS (Method 5): R_(t)=3.27 min.

MS (ESI pos): m/z=395 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.96 (s, 3H), 4.09 (s, 2H), 7.14-7.40 (7H),7.59 (dd, 1H), 8.26 (s, 1H), 12.55 (s, 1H) ppm.

Example 106-(3-Bromobenzyl)-1-(2-methylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

813 mg (3.78 mmol) of5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A) and3.90 g (17.03 mmol) of methyl (3-bromophenyl)acetate are dissolved in 15ml of absolute ethanol under argon, and 1.29 g (18.9 mmol) of sodiumethoxide are added. The reaction mixture is heated to a refluxovernight. Cooling to room temperature is followed by hydrolysis with 25ml of water and subsequent extraction with ethyl acetate (2×25 ml). Thecombined organic phases are dried over sodium sulphate, and the solventis distilled off under reduced pressure. The crude product is thenpurified by column chromatography (silica gel; mobile phasecyclohexane/ethyl acetate, gradient 10:1→1:1). 1.33 g (89% of theory) ofthe product are obtained.

LC-MS (Method 5): R_(t)=3.34 min.

MS (ESI pos): m/z=395 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.03 (s, 3H), 3.92 (s, 2H), 7.24-7.51 (7H),7.56 (m, 1H), 8.22 (s, 1H), 12.45 (s, 1H) ppm.

Exemplary embodiments 11-15 listed in Table 1 below are prepared inanalogy to the method of Example 10 starting from 100 mg (0.46 mmol) of5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A) with157 mg (2.31 mmol) of sodium ethoxide and with 2.08 mmol of the esterspecified in the table. The crude product is purified in each case viapreparative HPLC.

TABLE 1 MS: Ex. Yield R_(t) [min] m/z No. Structure Precursors [%](method) [M + H]⁺ 11

Example 25A, Methyl (3-trifluoromethyl- phenyl)acetate 60.1 2.04 (4) 38512

Example 25A, Methyl (2-methylphenyl)acetate 43.9 2.00 (4) 331 13

Example 25A, Methyl (2,4-dichloro- phenyl)acetate 39.2 2.15 (4) 386 14

Example 25A, Methyl (4- trifluoromethyl- phenyl)acetate 12.0 2.05 (4)385 15

Example 25A, Methyl (4- methylphenyl)acetate 34.8 1.98 (4) 331

Example 166-(3-Chlorobenzyl)-1-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 146 mg (60% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.69 mmol) of5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A),0.482 g (2.43 mmol) of ethyl (3-chlorophenyl)acetate and 0.139 g (3.47mmol) of 60% sodium hydride.

m.p.: 215° C.

MS (ESI pos): m/z=351 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.05 (s, 3H), 3.9 (s, 2H), 7.2-7.5 (m, 8H),8.25 (s, 1H), 12.5 (s, 1H) ppm.

Example 171-(2-Methylphenyl)-6-(2-pyridinylmethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 71 mg (40% of theory) of thedesired product are obtained as a colourless solid starting from 0.12 g(0.55 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide(Example 25A), 0.252 g (1.66 mmol) of ethyl (2-pyridinyl)acetate and0.111 g (2.77 mmol) of 60% sodium hydride.

m.p.: 162° C.

MS (ESI pos): m/z=318 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.0 (s, 3H), 4.2 (s, 2H), 7.2-7.5 (m, 6H),7.8 (t, 1H), 8.25 (s, 1H), 8.5 (d, 1H), 12.4 (s, 1H) ppm.

Example 186-(3-Chlorobenzyl)-1-(2-ethylphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 65 mg (27% of theory) of thedesired product are obtained as a colourless solid starting from 0.15 g(0.65 mmol) of 5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carboxamide(Example 26A), 0.398 g (1.95 mmol) of ethyl (3-chlorophenyl)acetate and0.130 g (3.26 mmol) of 60% sodium hydride.

m.p.: 208° C.

MS (ESI pos): m/z=365 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=0.9 (t, 3H), 2.35 (q, 2H), 3.9 (s, 2H),7.15-7.5 (m, 8H), 8.25 (s, 1H), 12.45 (s, 1H) ppm.

Example 196-(3-Chlorobenzyl)-1-(2-trifluoromethylphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 157 mg (70% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.56 mmol) of5-amino-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide (Example27A), 0.339 g (1.67 mmol) of ethyl (3-chlorophenyl)acetate and 0.111 g(2.78 mmol) of 60% sodium hydride.

m.p.: 152° C.

MS (ESI pos): m/z=405 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.9 (s, 2H), 7.15-7.5 (m, 4H), 7.6-8.05 (m,4H), 8.3 (s, 1H), 12.5 (s, 1H) ppm.

Example 206-(3-Chlorobenzyl)-1-(2-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 171 mg (73% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.66 mmol) of5-amino-1-(2-fluorophenyl)-1H-pyrazole-4-carboxamide (Example 28A),0.405 g (98% purity, 1.99 mmol) of ethyl (3-chlorophenyl)acetate and0.132 g (3.32 mmol) of 60% sodium hydride.

m.p.: 197° C.

MS (ESI pos): m/z=355 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.95 (s, 2H), 7.2-7.7 (m, 8H), 8.3 (s, 1H),12.5 (s, 1H) ppm.

Example 216-(3-Chlorobenzyl)-1-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 160 mg (70% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.63 mmol) of5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxamide (Example 29A),0.387 g (98% purity, 1.90 mmol) of ethyl (3-chlorophenyl)acetate and0.127 g (3.17 mmol) of 60% sodium hydride.

m.p.: 188° C.

MS (ESI pos): m/z=372 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.9 (s, 2H), 7.2-7.75 (m, 8H), 8.3 (s, 1H),12.5 (s, 1H) ppm.

Example 226-(3-Chlorobenzyl)-1-(2-pyridinyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 103 mg (41% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.74 mmol) of 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxamide(Example 30A), 0.451 g (98% purity, 2.21 mmol) of ethyl(3-chlorophenyl)acetate and 0.148 g (3.69 mmol) of 60% sodium hydride.

m.p.: 230° C.

MS (ESI pos): m/z=338 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=4.0 (s, 2H), 7.2-7.75 (m, 5H), 7.9-8.05 (m,2H), 8.3 (s, 1H), 8.6 (d, 1H), 12.5 (s, 1H) ppm.

Example 236-(3-Chlorobenzyl)-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In analogy to the preparation of Example 9, 180 mg (76% of theory) ofthe desired product are obtained as a colourless solid starting from0.15 g (0.65 mmol) of5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide (Example 31A),0.394 g (98% purity, 1.94 mmol) of ethyl (3-chlorophenyl)acetate and0.129 g (3.23 mmol) of 60% sodium hydride.

m.p.: 196° C.

MS (ESI pos): m/z=367 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.7 (s, 3H), 3.9 (s, 2H), 7.0-7.6 (m, 8H),8.2 (s, 1H), 12.4 (s, 1H) ppm.

1. A compound of formula (I):

in which R¹ is phenyl, pyridyl or thiophenyl which are optionallysubstituted by up to 3 substituents independently of one anotherselected from the group of C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl,cyano, trifluoromethyl, amino, nitro, hydroxy, C₁-C₆-alkylamino,halogen, C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino,C₁-C₆-alkylsulphonyl, and C₁-C₆-alkylthio, where C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkylamino, C₆-C₁₀-arylcarbonylamino,C₁-C₆-alkylcarbonylamino, C₁-C₆-alkylaminocarbonyl,C₁-C₆-alkoxycarbonyl, C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino, C₁-C₆-alkylsulphonyland C₁-C₆-alkylthio are optionally substituted by a radical selectedfrom the group of hydroxy, cyano, halogen, hydroxycarbonyl and a groupof the formula —NR³R⁴, where R³ and R⁴ are independently of one anotherhydrogen or C₁-C₆-alkyl, or R³ and R⁴ together with the nitrogen atom towhich they are bonded are 5- to 8-membered heterocyclyl, R² is phenyl orheteroaryl, where phenyl is substituted by 1 to 3 radicals andheteroaryl is optionally substituted by 1 to 3 radicals in each caseindependently of one another selected from the group of C₁-C₆-alkyl,C₁-C₆-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro,hydroxy, C₁-C₆-alkylamino, halogen, C₆-C₁₀-arylcarbonylamino,C₁-C₆-alkylcarbonylamino, C₁-C₆-alkylaminocarbonyl,C₁-C₆-alkoxycarbonyl, C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino, C₁-C₆-alkylsulphonyland C₁-C₆-alkylthio, where C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylamino,C₆-C₁₀-arylcarbonylamino, C₁-C₆-alkylcarbonylamino,C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl,C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₆-alkylsulphonylamino, C₁-C₆-alkylsulphonyland C₁-C₆-alkylthio are optionally substituted by a radicalindependently of one another selected from the group of hydroxy, cyano,halogen, hydroxycarbonyl and a group of the formula —NR³R⁴, where R³ andR⁴ have the meanings indicated above, or a salt, solvate or solvate of asalt thereof.
 2. The compound of claim 1, wherein: R¹ is phenyl, pyridylor thiophenyl, which are optionally substituted by up to 3 radicalsindependently of one another selected from the group of C₁-C₄-alkyl,C₁-C₄-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy,C₁-C₄-alkylamino, fluorine, chlorine, bromine, C₆-C₁₀-arylcarbonylamino,C₁-C₄-alkylcarbonylamino, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkoxycarbonyl, C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₄-alkylsulphonylamino,C₁-C₄-alkylsulphonyl, and C₁-C₄-alkylthio, where C₁-C₄-alkyl andC₁-C₄-alkoxy are optionally substituted by a radical selected from thegroup of hydroxy, cyano, fluorine, chlorine, bromine, hydroxycarbonyland a group of the formula —NR³R⁴, where R³ and R⁴ are independentlyhydrogen or C₁-C₄-alkyl, or R³ and R⁴ together with the nitrogen atom towhich they are bonded are 5- to 6-membered heterocyclyl, R² is phenyl,pyrimidyl or pyridyl, where phenyl is substituted by 1 to 3 radicals andpyrimidyl and pyridyl are optionally substituted by 1 to 3 radicals ineach case independently of one another selected from the group ofC₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl,amino, hydroxy, C₁-C₄-alkylamino, fluorine, chlorine, bromine,C₆-C₁₀-arylcarbonylamino, C₁-C₄-alkylcarbonylamino,C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkoxycarbonyl,C₆-C₁₀-arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylcarbonylamino, C₁-C₄-alkylsulphonylamino,C₁-C₄-alkylsulphonyl, and C₁-C₄-alkylthio, where C₁-C₄-alkyl andC₁-C₄-alkoxy are optionally substituted by a radical selected from thegroup of hydroxy, cyano, fluorine, chlorine, bromine, hydroxycarbonyland a group of the formula —NR³R⁴, where R³ and R⁴ have the meaningsindicated in claim 1, or a salt, solvate or solvate of a salt thereof.3. The compound of claim, wherein R¹ has the meaning indicated in claim1, and R² is phenyl or pyridyl, where phenyl is substituted by 1 to 2radicals and pyridyl is optionally substituted by 1 to 2 radicals ineach case independently of one another selected from the group ofmethyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine andchlorine, or a salt, solvate or solvate of a salt thereof.
 4. Thecompound of claim 1, wherein: R¹ is phenyl, pyridyl or thiophenyl, whichare optionally substituted by up to 2 radicals independently of oneanother selected from the group of C₁-C₄-alkyl, fluorine, chlorine,trifluoromethyl, hydroxy, phenylcarbonylamino, C₁-C₄-alkylcarbonylamino,C₁-C₄-alkylaminocarbonyl and phenylaminocarbonyl, R² is phenyl orpyridyl, where phenyl is substituted by 1 to 2 radicals and pyridyl isoptionally substituted by 1 to 2 radicals in each case independently ofone another selected from the group of methyl, ethyl, 2-propyl,trifluoromethyl, methoxy, ethoxy, fluorine and chlorine, or a salt,solvate or solvate of a salt thereof.
 5. A process for preparing acompound according to claim 1, which comprises: [A] converting acompound of the formula (II)

in which R² has the meaning indicated in claim 1, by reaction with acompound of the formula (IIIa)R¹—CH₂—C(O)-Z  (IIIa), in which R¹ has the meanings indicated in claim1, and Z is chlorine or bromine, in an inert solvent and in the presenceof a base, initially into compounds of the formula (IV)

in which R¹ and R² have the meaning indicated in claim 1, and thencyclizing in an inert solvent in the presence of a base to a compound ofthe formula (I), or [B] reacting compounds of the formula (II) with acompound of the formula (IIIb)R¹—CH₂—C(O)—OR³  (IIIb), in which R¹ has the meaning indicated in claim1, and R³ is methyl or ethyl, in an inert solvent and in the presence ofa base, with direct cyclization to (I), or [C] converting compounds ofthe formula (V)

in which R² has the meaning indicated in claim 1, initially by reactionwith a compound of the formula (IIIa) in an inert solvent and in thepresence of a base into a compound of the formula (VI)

in which R¹ and R² have the meaning indicated in claim 1, and cyclizingthe compound of formula (VI) in a second step in an inert solvent and inthe presence of a base and of an oxidizing agent to a compound offormula (I), and optionally reacting the resulting compounds of theformula (I) with the appropriate (i) solvents and/or (ii) bases or acidsto give the solvates, salt or solvate of a salt thereof.
 6. Apharmaceutical composition comprising at least one compound according toone of claims 1 to 4 and at least one pharmaceutically acceptable,essentially non-toxic carrier or excipient.
 7. A method for thetreatment an impairment of perception, concentration, learning and/ormemory in a human or animal comprising administering an effective amountof a compound of one of claims 1 to
 4. 8. The method of claim 7, wherethe impairment is a consequence of Alzheimer's disease.